PROJECT SUMMARY This proposal is built around our hypothesis that intra-prostatic androgens may be the link between two undisputable disparities in African American (AA) men; vitamin D deficiency and prostate cancer (PCa). We propose that the molecular response of prostate tissues to low vitamin D status leads to increased intracellular import of not only vitamin D, but also androgens. Megalin is the endocytic membrane receptor that imports globulin-bound vitamin D and androgens. We observed that in AA men only, the expression of prostatic megalin increased with vitamin D deficiency and increased with the percentage of West African Ancestry. We propose that long term vitamin D deficiency in AA men leads to a compensatory increase in megalin to maintain tissue levels when the serum is deficient. In turn, high megalin would also import more androgens, thus driving hormonal carcinogenesis. Hypothesis: Low vitamin D status in African American men drives increased androgen import into the prostate via the membrane endocytic receptor megalin. The objective is to both determine clinical significance and to delve into the mechanisms that regulate of hormone import. Specific Aim 1: To determine the relationship between intra-prostatic concentrations of androgens with vitamin D status in African American men. The effect of vitamin D deficiency on the serum and intra- prostatic distribution of androgens will be examined using an existing patient cohort. Specific Aim 2: To delineate the role of megalin-mediated endocytic transport in determining intracellular levels of androgens and vitamin D in human primary prostatic cells from African-American men. The results of Aim 1 will define the relationships between the hormones through correlative data. Whereas the experiments in Aim 2 will demonstrate that megalin is the mechanism of endocytic import for hormones using an in vitro model. Significance: This proposal addresses a knowledge gap with clear clinical implications for AA men. Although the disparity in vitamin D deficiency in AA is not disputable, the significance remains controversial given that AA men do not have altered bone health, which is a classical symptom of vitamin D deficiency. As well, the disparity in PCa in AA is not disputable and there are likely multiple biological contributors including socioeconomic status in many cases. Our findings may have wide implications to the clinical concern and management of vitamin D deficiency in AA men. Moreover, a proven link between vitamin D deficiency and hormone import may extend to other hormonal cancers. For example, megalin is also present in breast cancer and there is pronounced breast cancer disparity for African American women.